Long-term plasticity of neurons underlies adaptive changes in the brain. Appreciable gaps remain in our understanding of how cellular signaling cascades regulate the activity of key transcription factors, such as NFAT, that critically control plasticity. In keeping with our long-term objective of understanding mechanisms that regulate protein synthesis dependent plasticity, we aim to test models of NFAT function that, i) establish NFAT dependent regulation of neural development, ii) explore the role of NFAT in regulating neurotransmitter release, and iii) investigate NFAT function in activity-dependent plasticity and behavioral adaptation. Several advances put us in a unique position to analyze the role of NFAT in regulating long-term neuronal plasticity. First, we have conducted a genetic screen to identify transcription factors that regulate synaptic development and plasticity, leading to the isolation of NFAT. Second, we have created and validated a genetic model in which induction of neural activity stimulates ERK function through a canonical Ras pathway. This is particularly significant since in vivo models for activity-dependent plasticity are scarce. Our recent results show that NFAT constraints changes in synaptic size and strength in this model of plasticity. Third, we have established behavioral assays that test long-term adaptation, learning and memory formation. In the proposed work, we have outlined experiments that build on our preliminary data, and test our hypothesis that NFAT function in neurons regulates long-term behavioral adaptation. Specifically, we propose experiments i) to define the role of NFAT in the control of long-term olfactory habituation and, ii) to determine the extent to which NFAT regulates learning and memory formation in Drosophila. Upon conclusion, we hope to determine how NFAT activity in neurons regulates plasticity thereby controlling adaptive changes in the brain that underlie learning, addiction and neurological disease. PUBLIC HEALTH RELEVANCE: The proposed project aims to study cellular signaling and transcriptional mechanisms by which adaptive changes in the brain are brought about. Specifically, we aim to study the role of a transcription factor, NFAT in directing the ability of neurons to change in response to stimuli. Knowledge gained from this study will help us identify genetic and molecular pathways by which persistent alterations in neuronal circuits arise during learning, drug addiction and other neurological disorders.